Fludarabine and Rituximab With or Without Lenalidomide or Cyclophosphamide in Treating Patients With Symptomatic Chronic Lymphocytic Leukemia

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Eastern Cooperative Oncology Group
Southwest Oncology Group
NCIC Clinical Trials Group
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00602459
First received: January 23, 2008
Last updated: July 30, 2014
Last verified: May 2014
  Purpose

This randomized phase II trial studies how well fludarabine and rituximab with or without lenalidomide or cyclophosphamide works in treating patients with symptomatic chronic lymphocytic leukemia. Drugs used in chemotherapy, such as fludarabine and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Lenalidomide may stimulate the immune system in different ways and stop cancer cells from growing. Giving fludarabine and rituximab together with lenalidomide or cyclophosphamide may kill more cancer cells.


Condition Intervention Phase
B-cell Chronic Lymphocytic Leukemia
Stage I Chronic Lymphocytic Leukemia
Stage II Chronic Lymphocytic Leukemia
Stage III Chronic Lymphocytic Leukemia
Stage IV Chronic Lymphocytic Leukemia
Biological: rituximab
Drug: fludarabine phosphate
Drug: cyclophosphamide
Drug: lenalidomide
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Genetic Risk-Stratified, Randomized Phase II Study of Four Fludarabine/Antibody Combinations for Patients With Symptomatic, Previously Untreated Chronic Lymphocytic Leukemia

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • PFS rate [ Time Frame: Interval between randomization and progression or death, whichever comes first, assessed at 2 years ] [ Designated as safety issue: No ]
    Within each arm, the 2-year PFS will be tested to see whether it is significantly greater than the historical control rate. Rates within each arm will be estimated with their exact 90% confidence intervals. The chi-square test will be used to test whether the 2-year PFS of Arm B is significantly better than that of Arm A.


Secondary Outcome Measures:
  • Induction response rate (complete remission [CR] and partial remission [PR]) [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
    Induction response rates within each arm will be estimated with their exact 90% confidence intervals. For Arms A and C, induction response includes any responses occurring after the start of therapy; however, for Arms B and D, induction response includes only those responses occurring before the start of consolidation therapy with lenalidomide.

  • Time-to-progression [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
    The log-rank test will be used to test for arm differences in time-to-progression. A Kaplan-Meier analysis will be used to describe the entire distribution of time-to-progression within each arm.

  • PFS rate of patients with del(11q22.3) [ Time Frame: Interval between randomization and progression or death, whichever comes first, assessed at 2 years ] [ Designated as safety issue: No ]
    Two year PFS rate will be estimated with its 90% confidence interval for each arm, and the chi-square test will be used to test whether the 2-year PFS of Arm C is different from that of Arm D.

  • Induction response rates (CR + PR) in patients with del(11q22.3) [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
    Induction response rate will be estimated with its 90% confidence interval for each arm.

  • Time-to-progression in patients with del(11q22.3) [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
    A Kaplan-Meier analysis will be used to describe the distribution of time-to-progression within each arm and the log-rank test will be used to test for arm differences in time-to-progression.

  • Toxicity as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 16 months ] [ Designated as safety issue: Yes ]
    Each arm will be monitored for toxicities that cause a patient to go permanently off protocol therapy.

  • Interphase cytogenetic abnormalities [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
    Will be correlated with induction CR and PR and PFS. CR and PR rates will be estimated within marker-defined subgroups, and the difference in CR and PR rates between subgroups will be estimated with 95% confidence intervals.

  • IgVH gene mutational status [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
    Will be correlated with induction CR and PR and PFS. CR and PR rates will be estimated within marker-defined subgroups, and the difference in CR and PR rates between subgroups will be estimated with 95% confidence intervals.

  • CD38 expression [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
    Will be correlated with induction CR and PR and PFS. CR and PR rates will be estimated within marker-defined subgroups, and the difference in CR and PR rates between subgroups will be estimated with 95% confidence intervals.

  • CD49d expression [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
    Will be correlated with induction CR and PR and PFS. CR and PR rates will be estimated within marker-defined subgroups, and the difference in CR and PR rates between subgroups will be estimated with 95% confidence intervals.

  • ZAP-70 expression [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
    Will be correlated with induction CR and PR and PFS. CR and PR rates will be estimated within marker-defined subgroups, and the difference in CR and PR rates between subgroups will be estimated with 95% confidence intervals.

  • P53 dysfunction [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
    Will be correlated with induction CR and PR and PFS. CR and PR rates will be estimated within marker-defined subgroups, and the difference in CR and PR rates between subgroups will be estimated with 95% confidence intervals.

  • Change across time from baseline to progression in clonal evolution [ Time Frame: Baseline to up to 15 years ] [ Designated as safety issue: No ]
    Means/medians or proportions will be plotted against time. Analogous patient-specific plots will also be examined.

  • Change across time from baseline to progression in ZAP-70 expression [ Time Frame: Baseline to up to 15 years ] [ Designated as safety issue: No ]
    Means/medians will be plotted against time. Analogous patient-specific plots will also be examined.

  • Change across time from baseline to progression in p53 dysfunction [ Time Frame: Baseline to up to 15 years ] [ Designated as safety issue: No ]
    Proportions will be plotted against time. Analogous patient-specific plots will also be examined.

  • Change across time from baseline to progression in gene expression profile [ Time Frame: Baseline to up to 15 years ] [ Designated as safety issue: No ]
    Means/medians or proportions will be plotted against time. Analogous patient-specific plots will also be examined.

  • Change across time from baseline to progression in epigenetic changes in methylation [ Time Frame: Baseline to up to 15 years ] [ Designated as safety issue: No ]
    Means/medians or proportions will be plotted against time. Analogous patient-specific plots will also be examined.

  • Flow cytometry negativity [ Time Frame: Up to 24 months after study enrollment ] [ Designated as safety issue: No ]
    This objective will examine whether flow cytometry negativity at end of therapy and at 24 months after study enrollment correlates with PFS and OS. PFS and OS will be estimated with the Kaplan-Meier method within subgroups defined by flow cytometry status at 24 months after enrollment; PFS probabilities at given time points will be calculated with 95% confidence intervals. A covariate adjusted hazard ratio will be calculated with the proportional hazards model.


Estimated Enrollment: 405
Study Start Date: January 2008
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm A (rituximab, fludarabine phosphate)
Patients receive rituximab IV over 1-4 hours on days 1, 3, and 5 of course 1 and on day 1 of all subsequent courses. Patients also receive fludarabine phosphate IV over 30 minutes or PO on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression.
Biological: rituximab
Given IV
Other Names:
  • IDEC-C2B8
  • IDEC-C2B8 monoclonal antibody
  • Mabthera
  • MOAB IDEC-C2B8
  • Rituxan
Drug: fludarabine phosphate
Given IV or PO
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Other: laboratory biomarker analysis
Correlative studies
Experimental: Arm B (rituximab, fludarabine phosphate, lenalidomide)
Patients undergo RI therapy as in Arm I. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression. Patients with a complete or partial response or stable disease proceed to RC therapy beginning approximately 4 months after completing the last dose of fludarabine phosphate in course 6, comprising lenalidomide PO QD on days 1-21. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Biological: rituximab
Given IV
Other Names:
  • IDEC-C2B8
  • IDEC-C2B8 monoclonal antibody
  • Mabthera
  • MOAB IDEC-C2B8
  • Rituxan
Drug: fludarabine phosphate
Given IV or PO
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Drug: lenalidomide
Given PO
Other Names:
  • CC-5013
  • IMiD-1
  • Revlimid
Other: laboratory biomarker analysis
Correlative studies
Experimental: Arm C (rituximab, fludarabine phosphate, cyclophosphamide)
Patients receive rituximab IV over 4 hours on days 1 and 3 of course 1 and on day 1 of all subsequent courses. Patients then receive fludarabine phosphate IV piggyback over 30 minutes or PO followed by cyclophosphamide IV piggyback over 30 minutes on days 1-3. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression.
Biological: rituximab
Given IV
Other Names:
  • IDEC-C2B8
  • IDEC-C2B8 monoclonal antibody
  • Mabthera
  • MOAB IDEC-C2B8
  • Rituxan
Drug: fludarabine phosphate
Given IV or PO
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Other: laboratory biomarker analysis
Correlative studies
Experimental: Arm D (rituximab, fludarabine, cyclophosphamide, lenalidomide)
Patients receive the first course of RI therapy as in Arm A or B before being re-assigned to Arm D. Beginning in course 2, patients receive rituximab IV on day 1 and fludarabine phosphate IV piggyback over 30 minutes or PO and cyclophosphamide IV piggyback over 30 minutes on days 1-3. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression. Patients with a complete or partial response or stable disease proceed to RC therapy beginning approximately 4 months after completing the last dose of fludarabine phosphate in course 6, comprising lenalidomide PO QD on days 1-21. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Biological: rituximab
Given IV
Other Names:
  • IDEC-C2B8
  • IDEC-C2B8 monoclonal antibody
  • Mabthera
  • MOAB IDEC-C2B8
  • Rituxan
Drug: fludarabine phosphate
Given IV or PO
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Drug: lenalidomide
Given PO
Other Names:
  • CC-5013
  • IMiD-1
  • Revlimid
Other: laboratory biomarker analysis
Correlative studies

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Specific diagnosis of B-cell CLL:

    • An absolute lymphocytosis of > 5,000/μL

      • Morphologically, the lymphocytes must appear mature with < 55% prolymphocytes
      • Bone marrow examination must include at least a unilateral aspirate and biopsy; the aspirate smear must show > 30% of all nucleated cells to be lymphoid or the bone marrow core biopsy must show lymphoid infiltrates compatible with marrow involvement by CLL; overall cellularity must be normocellular or hypercellular
      • Local institution lymphocyte phenotype must reveal a predominant B-cell monoclonal population sharing a B-cell marker (cluster of differentiation [CD]19, CD20, CD23) with the CD5 antigen, in the absence of other pan-T-cell markers; additionally, the B-cells must be monoclonal with regard to expression of either kappa or lambda and have surface immunoglobulin expression of low density; patients with bright surface immunoglobulin levels must have CD23 co-expression
  • Patients must have symptomatic and active intermediate or high-risk categories of the modified three-stage Rai staging system:

    • Not eligible: low risk, Rai stage 0, lymphocytes (L) in blood (> 5000/uL) and marrow (> 30%) only
    • Intermediate risk, Rai stage I, L + enlarged lymph nodes (LN)
    • Intermediate risk, Rai stage II, L + spleen and/or liver (LN + or -)
    • High risk, Rai stage III, L + anemia (hemoglobin < 11 gm/dL)
    • High risk, Rai stage IV, L + thrombocytopenia (platelets < 100,000/uL)
  • Patients in the intermediate-risk group must have evidence of active disease as demonstrated by at least one of the following criteria:

    • Massive or progressive splenomegaly, hepatomegaly and/or lymphadenopathy
    • Presence of weight loss > 10% over the preceding 6 month period
    • Grade 2 or 3 fatigue
    • Fevers > 100.5°F or night sweats for greater than 2 weeks without evidence of infection
    • Progressive lymphocytosis with an increase of > 50% over a 2 month period or an anticipated doubling time of less than 6 months
  • No prior therapy for CLL, including no corticosteroids for autoimmune complications that have developed since the initial diagnosis of CLL
  • No medical condition requiring chronic use of oral corticosteroids
  • Performance status 0 - 2
  • Patients with human immunodeficiency virus (HIV) infection may be eligible provided they meet the following criteria: no evidence of infection with hepatitis B or C; CD4+ cell count > 350/mm^3; no evidence of resistant strains of HIV; if not on anti-HIV therapy, an HIV viral load < 10,000 copies HIV ribonucleic acid (RNA)/mL; if on HIV therapy, HIV viral load < 50 copies HIV RNA/mL; and no history of acquired immune deficiency syndrome (AIDS)-defining condition; patients receiving concurrent zidovudine or stavudine may not be enrolled
  • Non-pregnant and non-nursing
  • In females of child-bearing potential randomized to Arm B or assigned to Arm D, a negative urine or serum pregnancy test with a sensitivity of at least 25 mIU/mL will be required: 1) 10-14 days prior to beginning lenalidomide consolidation therapy; and 2) within 24 hours prior to the first dose of lenalidomide consolidation therapy; in addition, females of childbearing potential in Arm B and Arm D with regular menses must have a pregnancy test performed weekly during the first 28 days of treatment, and then every 28 days while taking lenalidomide (including breaks in lenalidomide), at discontinuation of lenalidomide, and then 28 days following discontinuation of lenalidomide; if menses are irregular, a pregnancy test must be performed weekly during the first 28 days of treatment, and then every 14 days while taking lenalidomide, at discontinuation of lenalidomide, and at 14 and 28 days after discontinuation of lenalidomide; additionally, females of childbearing potential must either commit to continued abstinence from heterosexual intercourse or begin TWO reliable methods of birth control - one highly effective method (intrauterine device [IUD], hormonal [birth control pills, injections, or implants], tubal ligation, or partner's vasectomy), and one additional effective method (latex condom, diaphragm, or cervical cap) - AT THE SAME TIME, at least 4 weeks before she begins lenalidomide therapy, while participating in the study, and for at least 4 weeks after completing lenalidomide therapy; "females of childbearing potential" is defined as a sexually mature woman who has not undergone a hysterectomy or bilateral oophorectomy, or who has had menses at any time in the preceding 24 consecutive months (not been naturally postmenopausal for at least 24 consecutive months)
  • Male patients randomized to Arm B or reassigned to Arm D must agree not to father a child and to use a latex condom during any sexual contact with females of childbearing potential while taking lenalidomide and for at least 4 weeks following completion of lenalidomide therapy, even if the patient have undergone a successful vasectomy
  • All patients randomized to Arm B or reassigned to Arm D must be counseled by a trained counselor every 28 days during consolidation therapy about pregnancy precautions and risks of fetal exposure
  • Creatinine =< 1.5 x upper limit of normal
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00602459

  Show 348 Study Locations
Sponsors and Collaborators
Eastern Cooperative Oncology Group
Southwest Oncology Group
NCIC Clinical Trials Group
Investigators
Principal Investigator: John Byrd Alliance for Clinical Trials in Oncology
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00602459     History of Changes
Other Study ID Numbers: NCI-2009-00441, NCI-2009-00441, NCIC CTG C10404, SWOG C10404, CAN-NCIC-CL3, CALGB-10404, CDR0000584205, ECOG 10404, ECOG-10404, NCIC-CTG-C10404, SWOG-C10404, CALGB 10404, CALGB-10404, U10CA031946, U10CA180821
Study First Received: January 23, 2008
Last Updated: July 30, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Leukemia, B-Cell
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Antibodies
Antibodies, Monoclonal
Cyclophosphamide
Fludarabine phosphate
Rituximab
Lenalidomide
Thalidomide
Fludarabine
Vidarabine
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Immunosuppressive Agents
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists

ClinicalTrials.gov processed this record on August 01, 2014